Goserelin is a synthetic decapeptide analogue of luteinizing hormone-releasing hormone (LHRH), also known as gonadotropin releasing hormone (GnRH) agonist analogue. On chronic administration Goserelin results in inhibition of pituitary luteinizing hormone secretion leading to a fall in serum testosterone concentrations in males and serum estradiol concentrations in females.
Goserelin is indicated in the palliative treatment of advanced carcinoma of the prostate as well as endometriosis. Goserelin has been approved in USA since 1989 as ZOLADEX® implant for subcutaneous implantation and is marketed by Astra Zeneca in the USA. It is available as ZOLADEX® 10.8 mg implant containing goserelin acetate equivalent to 10.8 mg of goserelin, designed for subcutaneous implantation with continuous release over a 12-week period and as ZOLADEX® 3.6 mg implant containing goserelin acetate equivalent to 3.6 mg of goserelin, designed for subcutaneous implantation with continuous release over a 28-day period.
ZOLADEX® is a 1 to 1.5 mm diameter cylinder, preloaded in a special single-use syringe with a 14-gauge to 16-gauge hypodermic needle. The main disadvantage related with ZOLADEX® is that it causes severe pain and haematomas when implanted into the patient. Hence, patient friendly mode of administration is not only desirable attribute but would also improve compliance to therapy.
U.S. Pat. No. 5,366,734 discloses the solid implant formulation of peptide and U.S. Pat. No. 5,004,602 discloses process for the preparation of such solid implant using melt extrusion in which freeze dried drug (peptide) and polymer has been extruded together under pressure at 70° C. to form a rod, from which implants of the required weight has been obtained. WO9324150 discloses composition in the form of microparticles or an implant containing salt of peptide with the polymer having carboxyl terminal group. U.S. Pat. No. 6,620,422 discloses dispersion of drug dispersed into polymer and use of such particles for the preparation of implant. During implant preparation, peptides and proteins are exposed to various unfavorable conditions. The exposure to high temperatures, shear forces, or high pressures may cause protein unfolding and irreversible aggregation. Further, complex manufacturing process for the solid implant by melt extrusion or injection moulding is difficult and requires tight process controls.
Various options have been explored to deliver controlled release goserelin such as microspheres, microparticles, nanoparticles etc, but production of microspheres is complex multiple step process involving optimization and control on many critical process parameters and high process loss add to the overall cost of the product.
Alternative approaches have been developed to overcome the shortcomings of solid implant, particularly pain at site of injection. U.S. Pat. No. 4,938,763 discloses method of forming in-situ implant containing biodegradable water insoluble polymer and biocompatible water soluble solvent. U.S. Pat. No. 5,077,049 discloses in-situ implant preparation containing biodegradable water insoluble polymer and biocompatible water soluble solvent for the periodontal pocket. U.S. Pat. No. 6,565,874 and U.S. Pat. No. 6,773,714 disclose in-situ implant composition of leuprolide acetate. US20040010224 discloses kits for the preparation of an in-situ implant composition containing biodegradable polymer and biocompatible solvents.
However, it has been found that the formed in-situ implants by above technologies, gives initial burst release and hence it is difficult to maintain constant plasma drug concentration throughout treatment regimen. Further, if the active agent is particularly toxic, this initial burst release of the active agent is likely to lead to increased incidences and magnitude of adverse drug reactions. To reduce this initial burst release various approaches have been developed by the scientists. For example, U.S. Pat. No. 5,702,716 discloses use of the rate-retarding agents such as ester of a mono, di or tricarboxylic acid, a polyhydroxy alcohol, a fatty acid, a fatty acid ester, an epoxidized oil, a sterol to retards the rate of release of the biologically active agent from the matrix. U.S. Pat. No. 5,744,153 discloses incorporation of drug into microstructures, such as lipospheres, liposomes, microcapsules, microparticles, and nanoparticles followed by suspending such drug containing microstructure into liquid implant forming composition. U.S. Pat. No. 6,630,155 discloses use of poly (lactide-co-glycolide)/polyethylene glycol (PLG/PEG) block copolymer to reduce the initial burst of biologically active agent released from the polymeric composition as it solidifies to form the solid implant upon administration. WO2005067889 discloses controlled release device comprising biodegradable polymer system of copolymers and polymeric blends comprising a hydrophobic component and a hydrophilic component to reduce burst effect or lag period. WO2008008363 discloses method of conjugating peptide with lipophilic moiety to reduce the initial burst release.
Applicant is unaware about any prior arts, which discloses pharmaceutical composition for the preparation of in-situ implant of goserelin which overcomes the above cited problems such as initial burst release. Moreover prior art uses complex & costly process, particularly the sterilization procedure is carried out using gamma-irradiation which has implications on polymer stability. Inventors of the present invention have surprisingly found the pharmaceutical composition of goserelin for the preparation of in-situ implant, which overcomes the above cited problems. Additionally, inventors have also discovered simpler and more efficient process for the preparation of the goserelin in-situ implant.